L34B - Drug Distribution 1 Flashcards
What is drug distribution?
The reversible transfer of drug from on site to another within the body
What are facts about blood circulation enables efficient drug distribution? (4) (numbers not asked)
- avg subject has 5L of blood = 3L plasma
- avg cardiac output is 5.5L/min at rest
- mixing of drug solution in the blood occurs very fast
- tissue distribution takes time, rate and extent depending on drug and tissues
What is cardiac output?
Amount of blood the heart pumps through the circulatory system in a minute
What is tissue differences in drug sitribution and blood circulation?
Some tissues haev more drug flow, so potentially more exposure to drugs
What are the distribution (potential) steps? (2)
- passage of capillary membrane
- passage of cell membrane
What is paracellular movement of drug influenced by?
Tighetness of the intercellular junctions
What are the 2 categories of transcellular pathways?
- those involving simple diffusion
- those involving facilitative mechs like transporters
What does movemenr of drugs across membrane occur through?
Paracellular ans transcellular pathways
What are the distribution processes? (3)
- passive diffusion
- transporters
- hydrostatic pressure
What is hydrostatic pressure like?
- arterial end pressure > tissue pressue
- tissue pressure > venous pressure
What is the movement like from capillaires to intersitial fluid (ISF)? (3)
- drug transport is independent of lipophilicity, charge and molecular size
- usually easy paracellular transport
- larger molecules, charge becomes more important (-ve = lower perm across renal glomerulus)
What is the movement like from interstitial fluid (ISF) to cells?
passage across is very dependent on:
- drug physicochemical properties (size, charge, lipophilicity)
- drug being subtrate for influx/efflux transporters
What is drug transport across blood-brain barrier, hepatocyte and renal tubule highly dependent on? (3)
- lipophilicity
- charge
- molecular size
What are the effects of charge like?
- large
- exceptions = paracellular transport across the blood capillary membranes and renal glomerulus)
What is membrane transport like for charged drugs?
Membrane transport is slower
- degree of ionisation at physiological pH determines movement across membranes
What is the pH partitiom hypothesis like?
- assumues only un-ionised drug penetrates membranes
- at eq, conc of unionised species are equal on both sides
- at eq, conc of ionised species is larger at the side with lower pH for a WB
- at eq, total conc is larger at side with lower pH
What is the pH in the body?
- gastric 1.5-7.0
- intestinal 6.2-7.5
- urine 5.0-7.5
- Elsewhere ~ pH of blooe (7.4)
- excp. Acidic intracellular lysosomal region (pH 5)
What are transporters like from blood to tissues, into cells and back?
- eq transporters vs active transporters/conc transporters
- efflux vs influx/uptake
- acpical side vs basolateral
What do transporters play an important role in?
- distribution of some drugs
- absorption and elimantion of some drugs
- therapy success - resistance of tumour cells to some drugs, acess to target site
What are transporters as part of the brain blood barrier like from blood to tissues, into cells and back?
- passage is highly dependent on lipophilicity, charge and molecular size
- permeability increases progessively with increasgin lipophilicity (not always)
- vinblastine and vincristine have permeability lower than expected, due to efflux PGP
What can drugs bind to?
- tissue components
- plasma proteins
- RBCs
What is the binding eq in plasma like?
- very fast
- usually reversible
- dif drugs bind to dif plasma proteins (acidic drugs to albumin, basic drugs to a1-acid glycoprotein, neutral compounds to lipoproteins)
What can bound drugs not do?
Diffuse across biological membranes - cannot cross capillary membranes
What is plasma binding a key determinant of?
Drug distribution
What is the degree of binding for a drug expressed as?
Bound fraction (fbound)
Fbound = [drug]bound/[drug]total
What is free conc of a drug in plasma?
Cfree = Ctotal x Fu
How does drug binding modify drug distribution? (3)
- complex [drug-protein] too large to diffuse across membrane
- only free drug is able to distribute out of plasma
- drug distribution is V dependent on the drugs binding affinity to BOTH plasma and tissue components
What are the different ways drug can binf to tissues? (3)
- drug neither bind to plasma proteins nor tissues
- drugs binds to plasma proteins but not to tissues
- drug binds to tissue components but not to plasma proteins
What is affininty for a tissue better described by as for some drugs?
Partitioning phenomena rather than binding process
How can you descrube the affinity through a partition coefficient?
Ptissue/blood = Cdrug,tissue/Cdrug,plasma
